[go: up one dir, main page]

US7351863B2 - Method of fluorination - Google Patents

Method of fluorination Download PDF

Info

Publication number
US7351863B2
US7351863B2 US10/537,437 US53743705A US7351863B2 US 7351863 B2 US7351863 B2 US 7351863B2 US 53743705 A US53743705 A US 53743705A US 7351863 B2 US7351863 B2 US 7351863B2
Authority
US
United States
Prior art keywords
group
fluorination
reaction
monosaccharide
microwave
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related, expires
Application number
US10/537,437
Other languages
English (en)
Other versions
US20060014972A1 (en
Inventor
Shoji Hara
Tsuyoshi Fukuhara
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mitsubishi Gas Chemical Co Inc
Original Assignee
Mitsubishi Gas Chemical Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP2002352968A external-priority patent/JP4577478B2/ja
Priority claimed from JP2002358249A external-priority patent/JP2004189655A/ja
Application filed by Mitsubishi Gas Chemical Co Inc filed Critical Mitsubishi Gas Chemical Co Inc
Assigned to MITSUBISHI GAS CHEMICAL COMPANY, INC. reassignment MITSUBISHI GAS CHEMICAL COMPANY, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FUKUHARA, TSUYOSHI, HARA, SHOJI
Publication of US20060014972A1 publication Critical patent/US20060014972A1/en
Priority to US12/068,500 priority Critical patent/US7892518B2/en
Priority to US12/068,481 priority patent/US7968751B2/en
Application granted granted Critical
Publication of US7351863B2 publication Critical patent/US7351863B2/en
Adjusted expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/30—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B39/00—Halogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C07C17/18—Preparation of halogenated hydrocarbons by replacement by halogens of oxygen atoms of carbonyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/64—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by simultaneous introduction of -OH groups and halogens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/58—Preparation of carboxylic acid halides
    • C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/08—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
    • C07H9/04—Cyclic acetals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/09—Geometrical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered
    • C07C2601/20—Systems containing only non-condensed rings with a ring being at least seven-membered the ring being twelve-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the present invention relates to a method of fluorination. More particularly, the present invention relates to a method of selectively fluorinating saccharides useful as the functional chemicals such as materials for drugs, cosmetics and healthy foods, and a method of efficiently fluorinating a substrate by bringing the substrate into reaction with a fluorinating agent under irradiation with microwave or electromagnetic wave having a wavelength around the microwave region.
  • Examples of the method using a nucleophilic fluorinating agent include fluorination of sugars by the halogen-fluorine exchange such as the halogen-fluorine exchange of a compound having a halogen atom activated by carbonyl group at the ⁇ -position, the halogen-fluorine exchange of trichloropyrimidine and the halogen-fluorine exchange of a sugar triflate; synthesis of fluoroethanols by ring-opening fluorination of oxirane compounds (formation of a fluorohydrin); formation of halofluoro group or fluorosulfenyl group in unsaturated compounds; synthesis of fluorobenzene by fluorination accompanied with removal of diazo group; gem-difluorination of 1,3-dithiolanes and hydrazones; and the reaction of removing protective group of silyl ethers.
  • fluorination of sugars by the halogen-fluorine exchange such as the hal
  • saccharides As for saccharides, a wide range of application and development are expected since saccharides play important roles in the activities of the life such as the communication between cells and the mechanism of immunity as the energy source and as the sugar chain in proteins and have the ability of forming organs such as skins and bones.
  • chitosan which is a high order condensate having a repeating unit of glucosamine and is produced by hydrolysis or fermentation of crustaceans or glucose as the material, is used as an additive, an antiseptic or a pet food in the field of foods and as an artificial skin, a stitching thread, a membrane for artificial dialysis and a film for controlled release in the field of medical treatments.
  • Chitosan is also used in the field of the drug as an anticancer agent, an immunostimulator, an agent for suppressing blood glucose elevation and an agent for suppressing cholesterol absorption, in the field of the agriculture as an agent for soil amelioration, an antivirus agent and an insecticide, in the field of industry as soap, a hair tonic, a cosmetic and a tooth paste, and in the field of the environment as an agent for trapping waste fluids and an agent for treating heavy metals and waste water.
  • saccharides As described above, as the application of saccharides, the development of products having useful functions in the fields of foods, drugs, medical treatments, agriculture, industry and environment is promoted by bonding specific monosaccharides in higher orders or by introducing amino group, acetyl group or fluorine atom into saccharides.
  • fluorinated sugars obtained by fluorinating saccharides exhibiting excellent adaptability to the human body are actively studied for application as the anticancer agent and an immunosuppressant.
  • the method of fluorination used for this purpose include the direct fluorination with the fluorine gas, the method of halogen-fluorine exchange, the method using hydrogen fluoride and a base such as pyridine and triethylamine, and the method using a fluorinating agent such as IF 5 , SF 4 , DAST and the Yarovenko reagent.
  • the object reaction does not proceed when the combination of HF and a base which is a convenient fluorinating agent such as the HF-pyridine complex compound and the HF-triethylamine complex compound is used.
  • a base which is a convenient fluorinating agent such as the HF-pyridine complex compound and the HF-triethylamine complex compound is used.
  • side reactions such as scission of the protective group take place.
  • the present invention has an object of overcoming the above problems and providing a method of making the fluorination of a desired substrate proceed highly selectively, efficiently and safely, and to provide a method of fluorinating a specific position of a saccharide selectively without affecting a protective group at a temperature within a wide range safely and easily.
  • the present invention provides:
  • polyalcohols and other substances can be used as the saccharide used in the present invention.
  • the other substances include monosaccharides such as glucose, fucose, N-acetylglucosamine, N-acetylgalactosamine, N-acetylneuraminic acid, erythrose, threose, ribose, arabinose, xylose, arose, lyxose, altrose, mannose, gulose, idose, galactose, talose, psicose, furctose, sorbose, tagatose, unsaturated sugars having an unsaturated bond such as hexaenose, branched sugars such as apiose, and derivative of sugars such as deoxy sugars, amino sugars, thio sugars, condensed sugars and anhydrides of monosaccharides; oligosaccharides, including disaccharides, comprising two to
  • the fluorinating agent used for fluorination of the above saccharides is a compound represented by the following general formula (I):
  • R 0 , R 1 and R 2 represent hydrogen atom or an alkyl or aryl group which may have substituents, the atom and the groups represented by R 0 , R 1 and R 2 may be the same with or different from each other, and two or three of the groups represented by R 0 , R 1 and R 2 may be bonded to each other to form a ring.
  • alkyl group saturated and unsaturated aliphatic and alicyclic alkyl groups having 1 to 32 carbon atoms are preferable.
  • alkyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, t-butyl group, pentyl group, hexyl group, heptyl group, octyl group, 2-ethylhexyl group, nonyl group, decyl group, cyclohexyl group, cyclooctyl group, decalyl group, norbornyl group, bicyclohexyl group, adamantyl group, isomers of these groups, hydroxymethyl group, hydroxyethyl group, hydroxypropyl group and hydroxybutyl group.
  • aryl group examples include aromatic aryl groups such as phenyl group, o-tolyl group, m-tolyl group, p-tolyl group, o-xylyl group, m-xylyl group, p-xylyl group, dimethylphenyl group, isomers of dimethylphenyl group having methyl group at different positions, cumyl group, mesityl group, trimethylphenyl group, hydroxyphenyl group, methoxyphenyl group, isomers of methoxyphenyl group having methoxyl group at different positions, naphthyl group, methylnaphthyl group, dimethylnaphthyl group, hydroxynaphthyl group, biphenyl group, tetralyl group, terphenyl group, anthryl group, benzothienyl group, chromenyl group, indolyl group, pyridyl group and quinolyl group; and groups having
  • the alkyl group and the aryl group may have other functional groups such as hydroxyl group, halogen groups, nitro group, mercapto group, amino group, amide group, cyano group, carbonyl group, carboxyl group, acetyl group, acyl group, alkoxyl groups and sulfone group.
  • N,N-diethyl- ⁇ , ⁇ -difluoro(3-methyl)benzylamine and N,N-diethyl- ⁇ , ⁇ -difluoro(2-methoxy)benzylamine which are compounds represented by general formula (I) in which R 0 represents 3-methylphenyl group or 2-methoxyphenyl group, and R 1 and R 2 represent ethyl group, are more preferable since the compounds exhibit the excellent heat stability such that the compounds are stable at a high temperature of 150° C. or higher.
  • the fluorinating agent represented by general formula (I) is used in an amount of 1 mole or more per 1 mole of the functional group in the substrate taking part in the reaction.
  • the reaction may be allowed to proceed while the fluorinating agent is used in an excess amount or in an amount less than the stoichiometry.
  • the fluorination can be conducted in accordance with a batch process, a semi-batch process or a continuous process.
  • the fluorination can be conducted in accordance with the conventional thermal reaction or under irradiation with microwave and/or electromagnetic wave having a wavelength around the microwave region.
  • the reaction can be safely performed when the temperature of the reaction is lower than the so-called runaway temperature under heating (the temperature at which the heat generation starts in the ARC test). It is preferable that the fluorination is conducted at 200° C. or lower and more preferably at a temperature in the range of the room temperature to 150° C. When the thermal reaction is conducted, the fluorination is conducted at a temperature lower than the runaway temperature under heating.
  • microwave having a frequency of 1 to 30 GHz is used.
  • Electromagnetic wave having a frequency outside the above range such as millimeter wave having a frequency greater than 30 GHz and 300 GHz or smaller and electromagnetic wave having a frequency in the range of 0.3 GHz or greater and smaller than 1 GHz can also be used.
  • the electromagnetic wave can be applied continuously or intermittently while the temperature is adjusted.
  • a conventional reactor for batch reactions is covered with a shield so that the microwave does not leak, and microwave is applied to the reactor.
  • a commercial microwave oven is advantageously used, and a commercial oven for chemical synthesis may be used.
  • the output of the magnetron tube for generation of microwave used for the reaction and the intensity of the irradiation are not particularly limited except the legal restrictions.
  • An easily available tube having an output of 200 to 6,000 W is preferable.
  • a plurality of tubes may be used in combination when a greater output is necessary.
  • the intensity of the irradiation with microwave is, in general, 20 W/cm 2 or greater and more preferably 100 W/cm 2 or greater.
  • the time of the reaction is in the range of 10 to 360 minutes when the thermal reaction is conducted.
  • the time of the reaction is shorter than that in the thermal reaction.
  • the time of the irradiation is 0.1 to 200 minutes, more preferably 0.1 to 60 minutes and most preferably 1 to 30 minutes although the time of the irradiation is different depending on the type of the substrate.
  • microwave may be applied for 3 hours or longer, where necessary.
  • the reaction may be conducted at a temperature in a range such that the substrate, the fluorinating agent and the reaction products are stable.
  • a temperature in the range of the room temperature of about 25° C. to 200° C. is preferable.
  • the reaction may be conducted at a temperature lower than the room temperature or higher than 200° C.
  • a solvent may be used for conducting the stirring sufficiently or preventing elevation of the temperature.
  • the preferable solvent include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, aromatic halogenated hydrocarbons, nitrites and ethers which are inter to the substrate, the fluorinating agent and the reaction products.
  • a suitable combination of the solvents may be used.
  • the reaction product When the irradiation with microwave is completed, the reaction product may be separated after treatments such as post treatments, extraction, distillation and filtration similarly to the treatments in the ordinary thermal reaction.
  • the above method of fluorination comprising conducting the reaction under irradiation with microwave and/or electromagnetic wave having a wavelength around the microwave region can be applied to fluorination of substrates other than saccharides using a fluorinating agent other than the fluorinating agent represented by general formula (I).
  • a fluorinating agent represented by general formula (II):
  • X represents hydrogen atom or a halogen atom
  • R 0 , R 1 and R 2 and Y are as defined for general formula (I).
  • R 3 , R 4 and R 5 each independently represent an alkyl or aryl group which may have substituents, and two or three of the groups represented by R 3 , R 4 and R 5 may be bonded to each other to form a ring structure.
  • Examples of the alkyl group and the aryl group represented by R 3 , R 4 and R 5 include the groups described as the examples of the alkyl groups and the aryl groups represented by R 0 , R 1 and R 3 in general formula (I).
  • X represents hydrogen atom or a halogen atom such as fluorine atom, chlorine atom, bromine atom and iodine atom.
  • R 3 represents an aryl group which may have substituents
  • X represents fluorine atom
  • R 4 and R 5 represent an alkyl group or aryl group having 1 to 32 carbon atoms which may have substituents.
  • Examples of the compound represented by general formula (III) include alkylfluoroamines and arylfluoroamines.
  • Examples of the compound represented by general formula (III) in which R 4 and R 5 represent ethyl group include N,N-diethyl- ⁇ , ⁇ -difluorobenzylamine, N,N-diethyl- ⁇ , ⁇ -difluoro(2-methyl)benzylamine, N,N-diethyl- ⁇ , ⁇ -difluoro-(3-methyl)benzylamine, N,N-diethyl- ⁇ , ⁇ -difluoro(4-methyl)benzylamine, N,N-diethyl- ⁇ , ⁇ -difluoro(2-methoxy)benzylamine, N,N-diethyl- ⁇ , ⁇ -difluoro(4-phenyl)benzylamine, N,N-diethyl- ⁇ , ⁇ -difluorocylcohexylmethylamine, N,
  • aromatic fluoroamines such as N,N-diethyl- ⁇ , ⁇ -difluoro(3-methyl)-benzylamine, N,N-diisopropyl- ⁇ , ⁇ -difluoro(3-methyl)benzylamine, N,N-diethyl- ⁇ , ⁇ -difluoro(2-methoxy)benzylamine, N,N-diisopropyl- ⁇ , ⁇ -difluoro-(2-methoxy)benzylamine and N,N-di-n-butyl- ⁇ , ⁇ -difluoro(2-methoxy)-benzylamine are preferable due to the excellent heat stability.
  • the substrates which can be fluorinated with the fluorinating agent represented by general formula (III) are organic compounds, polymers and inorganic compounds.
  • the substrates are so numerous that it is difficult that examples corresponding to the entire substrates are shown.
  • the substrate is an organic compound having oxygen atom, nitrogen atom or sulfur atom.
  • organic compound examples include primary, secondary and tertiary alcohols having isolated hydroxyl groups as the functional groups; polyols having a plurality of hydroxyl groups such as 1,2-diols having adjacent hydroxyl groups, 1,3-diols and other polyols; thiols; compounds having carbonyl group or carboxyl group such as aldehydes, ketones, carboxylic acids, hydroxycarboxylic acid, esters of carboxylic acids and lactones; aromatic compounds exhibiting an increased nucleophilicity due to the presence of an electron-attracting group such as cyanohydrins, sulfonic acids, esters of sulfonic acids, thiocarboxylic acids, esters of thiocarboxylic acids and dinitrobenzenes; aromatic diazonium salts; heterocyclic compounds; saccharides such as monosaccharides, glycoxides, anhydrides of monosaccharides, oligosaccharides and polysaccharides; hydrocarbon
  • the substrate include ethanol, propyl alcohol, butyl alcohol, heptanol, octanol, benzyl alcohol, phenetyl alcohol, nitrophenol, cyclohexanol, adamantanol, cholesterol, epiandrostrone, ethylene glycol, cyclohexanediol, glycerol, propylene oxide, alkyloxiranes, benzaldehyde, alkylbenzaldehydes, acetophenone, benzophenone, cyclopentanone, cyclohexanone, indanone, mandelonitrile, ⁇ -butyrolactone, mevalonolactone, benzenesulfonic acid, naphthalene-sulfonic acid, thiobenzoic acid, methyl thiobenzoate, dinitrochlorobenzene, ⁇ -glucopyranose, ⁇ -D-fructofuranose, ⁇
  • Examples of the specific compound providing a greater added value include 2-hydroxymethyl-saccharine as the raw material of 2-saccharinylmethylarylcarboxylates useful as the inhibitor for proteolysis enzymes, 2,3-di(4-pyridyl)-4-methylthiophene-3-carboaldehyde as an intermediate for pyridylthiophene used for curing diseases occurring via cytokine, dinucleotides and oligonucleotides used as the drug for curing diseases caused by viruses such as herpes, and 7 ⁇ -carboxymethyl-4-aza-5 ⁇ -cholestanone used as a raw material for the inhibitor for 5 ⁇ -reductase.
  • the substrate used for fluorination using the fluorinating agent represented by general formula (III) is not limited to the compounds shown as the examples.
  • the substrates compounds having hydroxyl group, saccharides, compounds having carbonyl group or carboxyl group and epoxides are preferable.
  • the compounds having hydroxyl group compounds having adjacent hydroxyl groups are more preferable.
  • the procedures for fluorination using the fluorinating agent represented by general formula (III) under irradiation with microwave and/or electromagnetic wave having a wavelength around the microwave region are approximately the same as those for fluorination using the fluorinating agent represented by general formula (I) under irradiation with microwave and/or electromagnetic wave having a wavelength around the microwave region.
  • the temperature of the reaction can be selected in a range such that the substrate, the fluorinating agent and the reaction products are stable. In general, a temperature in the range of the room temperature of about 25° C. to 200° C. is preferable. However, the reaction may be conducted at a temperature lower than the room temperature or higher than 200° C.
  • the fluorinating agent represented by general formula (I) in which Y represents nitrogen atom or when the fluorinating agent represented by general formula (III) is used the fluorinating agent can be recovered as the corresponding amide after the fluorination has been completed, and a process for fluorination allowing recycling of the materials can be constructed easily.
  • the above substrate can be fluorinated efficiently in a short time safely with the excellent selectivity.
  • the method of fluorination under irradiation with microwave and/or electromagnetic wave having a wavelength around the microwave region can be applied to fluorination using a complex compound comprising HF and a base as the fluorinating agent.
  • the complex compound comprising HF and a base used as the fluorinating agent examples include alkylamine-HF complex compounds, melamine-HF complex compounds and pyridine-HF complex compounds.
  • the triethylamine-nHF complex compounds (in general, n represents an integer) are preferable, and the triethylamine-3HF complex compound is more preferable due to the easiness of handling since the compound can be distilled and glass vessels can be used due to the absence of the corrosive property.
  • an agent accelerating the reaction may be used in combination with the fluorinating agent to accelerate the reaction.
  • the agent accelerating the reaction NBS (N-bromosuccinimide), DBH (1,3-dibromo-5,5-dimethylhidantoin) and sulfur chloride are used for the gem-difluorination of 1,3-dithiane, and sulfuryl compounds are used in combination with the complex compound of HF and a base for obtaining halofluorides or fluorosulfenyl compounds from olefins and alkynes.
  • Examples of the substrate used in the method of fluorination using the complex compound of HF and a base as the fluorinating agent under irradiation with microwave and/or electromagnetic wave having a wavelength around the microwave region include compounds having hydrogen atom activated by a substituent at the a position, the Deposition or the ⁇ -position, silyl ether compounds, compounds having an unsaturated group, hydroxyl group, a halogeno group, amino group, diazo group, triazeno group or isocyano group as the functional group, and cyclic compounds having three-membered or greater ring which may have heteroatoms.
  • the above substrates are compounds which can take part in reactions such as conversion of functional groups into fluorine, ring-opening fluorination of cyclic compounds, gem-difluorination of 1,3-dithiolane and hydrazone, gem-trifluorination of ortho-thioesters, oxidative fluorination, reductive fluorination and reaction of removing the protective group of silyl ethers.
  • Examples of the conversion of functional groups into fluorine include the halogen-fluorine exchange with halogen compounds, formation of halofluorides, fluorosulfenyl compounds and nitrofluoro compounds from unsaturated groups in olefins and alkynes, fluorination of hydroxyl groups in alcohols and saccharides and fluorination of amino group, diazo group, triazeno group and isocyano group with removal of diazo group.
  • cyclic compounds which may have heteroatoms such as cyclopropane, cyclobutane, cyclopentane, cyclobutene, cylopentene, cyclohexene, cycloheptene, cyclooctene, cyclodecene, cyclododecene, butene, 2,3-dimethylbutene, methylenecyclohexene, 5- ⁇ -cholest-2-ene, ethylene oxide, propylene oxide, oxetane, oxorane, cyclohexene oxide, cyclooctene oxide, cyclodecene oxide, cyclododecene oxide, alkyloxiranes, styrene oxide, norbornene oxide, aziridine, azirine, thiirane, azethidine, azolidine, thiazolidine, 1,3-dithiane; aromatic compounds
  • Examples of the other functional group include a single or a plurality of hydroxyl groups, thiol groups, formyl groups, carbonyl groups, carbonyloxyl groups, alkyloxycarbonyl groups, cyano groups, sulfonyl groups, alkylsulfonyl groups, sulfenyl groups, thiocarbonyl groups, nitro groups, amino groups and diazo groups, which may be primary, secondary or tertiary groups.
  • the above method can be applied not only to organic compounds, but also to inorganic compounds, materials obtained by introducing the functional group on the surface of polymers and organic-inorganic hybrid materials obtained by introducing the functional group.
  • the substrate used for fluorination using the complex compound of HF and a base under irradiation with microwave and/or electromagnetic wave having a wavelength around the microwave region is not limited to the compounds shown as the examples.
  • saccharides and cyclic compounds having cyclopropane ring, oxirane ring, aziridine ring, azirine ring or 1,3-dithiane ring are preferable among these substrates.
  • the procedures for fluorination using the complex compound of HF and a base under irradiation with microwave and/or electromagnetic wave having a wavelength around the microwave region are approximately the same as those for fluorination using the fluorinating agent represented by general formula (I).
  • the temperature of the reaction can be selected in a range such that the substrate, the fluorinating agent and the reaction products are stable. In general, a temperature in the range of the room temperature of about 25° C. to 300° C. is preferable. However, the reaction may be conducted while the temperature is controlled at a value lower than the room temperature or higher than 200° C. similarly to the ordinary thermal reaction.
  • the complex compound of HF and a base When the complex compound of HF and a base is used as the fluorinating agent under irradiation with microwave and/or electromagnetic wave having a wavelength around the microwave region, the complex compound of HF and a base which is stable and causes practically no corrosion, such as the triethylamine-HF complex, can be used in various types of fluorination for various substrates, and the fluorinationi can be conducted efficiently in a short time under a milder condition than that of the thermal reaction.
  • Examples of the above fluorination include the ring-opening fluorination of compounds having hydrogen atom activated by a substituent at the a position, the ⁇ -position or the ⁇ -position, silyl ether compounds, compounds having an unsaturated group, hydroxyl group, a halogeno group, amino group or diazonium group as the functional group, and cyclic compounds having three-membered or greater ring which may have heteroatoms, formation of halofluorides or fluorosulfenyl compounds from unsaturated compounds, the halogen-fluorine exchange, fluorination with removal of diazo group, gem-difluorination of 1,3-dithioranes and hydrazones and the removal of the protective group of silyl ethers.
  • the formed white precipitates were separated by filtration, washed with carbon tetrachloride and n-hexane and dried, and N,N-diethyl- ⁇ -chloro-meta-toluylamidium chloride was obtained.
  • the obtained N,N-diethyl- ⁇ -chloro-meta-toluylamidium chloride was heated slowly in a capillary tube (a sealed tube) to 200° C. No decomposition was observed, and the compound was thermally stable.
  • N,N-diethyl- ⁇ -chloro-meta-toluylamidium chloride had a melting point of 54.6° C. in accordance with the thermal analysis using TG-DTA.
  • N,N-diethyl- ⁇ -chloro-meta-toluylamidium chloride 25 g; 0.1 mole
  • a spray dried product of potassium fluoride manufactured by MORITA KAGAKU Co., Ltd.; 23.5 g; 0.4 moles
  • acetonitrile 250 g
  • the obtained fraction was a colorless transparent liquid and had the following properties.
  • a sample of the product was slowly heated in a capillary tube (a sealed tube) to 200° C. and kept at this temperature for 1 hour. No decomposition was observed, and the product was thermally stable.
  • heat generation started at 210° C., and a gradual decrease in the weight was observed.
  • the peak temperature of the heat generation was 280° C.
  • the temperature of the start of heat generation was 180° C. as measured in accordance with the method of measuring the runaway reaction of Japanese Industrial Standard (the ARC test) for evaluating the heat stability of a substance in the adiabatic condition.
  • a toluene solution (56 g) containing diethylamine (25.80 g; 0.352 moles) was placed. While the flask was cooled with ice water and the solution was stirred, a toluene solution (30 g) of 2-methoxybenzoyl chloride (2.00 g; 0.117 moles) was added dropwise over 30 minutes. After the addition was completed, water was added to the resultant mixture, and diethylamine and diethylamine hydrochloride in excess amounts were removed. The obtained toluene layer was dehydrated with MgSO 4 . Then, the solvent was removed by distillation, and a light yellow liquid was obtained (the obtained amount: 22.81 g; the yield: 94%).
  • N,N-diethyl- ⁇ -chloro(2-methoxyphenyl)amidium chloride prepared above (20.00 g; 0.0725 moles), potassium fluoride (manufactured by MORITA KAGAKU SPRAY DRY Co., Ltd.; 17.72 g; 0.3052 moles) and acetonitrile (200 g) were placed into a three-necked flask (100 ml). Under the atmosphere of nitrogen, a condenser and an electromagnetic stirrer were attached to the flask, and the reaction was allowed to proceed at 80° C. for 20 hours.
  • reaction mixture was cooled to the room temperature and filtered in the glove box, and an acetonitrile solution containing a product of fluorine exchange with N,N-diethyl- ⁇ -chloro(2-methoxyphenyl)amidium chloride was obtained.
  • the obtained fraction was colorless transparent liquid and had the following properties.
  • a sample of the product was slowly heated in a capillary tube (a sealed tube) to 200° C. and kept at this temperature for 1 hour. No decomposition was observed, and the product was thermally stable.
  • heat generation started at 20 to 210° C., and a gradual decrease in the weight was observed.
  • the peak temperature of the heat generation was 255° C.
  • the temperature of the start of heat generation was 159° C. as measured in accordance with the method of measuring the runaway reaction of Japanese Industrial Standard (the ARC test) for evaluating the heat stability of a substance in the adiabatic condition.
  • a 100 ml glass reactor equipped with a stirrer and a condenser and coated with a fluororesin was used.
  • methyl 2,3-O-isopropylidene- ⁇ -D-ribofuranoside (10 mmole) as the substrate
  • N,N-diethyl- ⁇ , ⁇ -difluoro(3-methyl)benzylamine (12 mmole; 2.56 g) as the fluorinating agent and 20 ml of heptane were placed. While the resultant mixture was stirred, the temperature was raised from the room temperature to 100° C., and the reaction was allowed to proceed for 60 minutes.
  • a 100 ml glass reactor equipped with a stirrer and a condenser and coated with a fluororesin was placed.
  • a 100 ml glass reactor equipped with a stirrer and a condenser and coated with a fluororesin was placed.
  • methyl 2,3-O-isopropylidene- ⁇ -D-ribofuranoside (10 mmole; 2.04 g) as the substrate and N,N-diethyl- ⁇ , ⁇ -difluoro(3-methyl)benzylamine (12 mmole; 2.56 g) as the fluorinating agent were placed.
  • 2,3-O-Isopropylidene-5-deoxy- ⁇ -D-furanosyl fluoride was obtained as the product of rearrangement at a yield of 55%.
  • methyl 2,3-O-isopropylidene-5-deoxy-5-fluoro- ⁇ -D-ribofuranoside of the object compound was not obtained at all.
  • Example 2 The same procedures as those conducted in Example 2 were conducted except that ethyl 2,3-O-isopropylidene- ⁇ -D-ribofuranoside (10 mmole) as the substrate and N,N-diethyl- ⁇ , ⁇ -difluoro(3-methyl)-benzylamine (20 mmole) as the fluorinating agent were used.
  • ethyl 2,3-O-isopropylidene-5-deoxy-5-fluoro- ⁇ -D-ribofuranoside was obtained at a yield of 55%
  • 2,3-O-isopropylidene-5-O-ethyl- ⁇ -D-furanosyl fluoride was obtained at a yield of 21%.
  • Example 3 The same procedures as those conducted in Example 3 were conducted except that isopropyl 2,3-O-isopropylidene- ⁇ -D-ribofuranoside (10 mmole) was used as the substrate.
  • isopropyl 2,3-O-isopropylidene-5-deoxy-5-fluoro- ⁇ -D-ribofuranoside was obtained at a yield of 62%
  • 2,3-O-isopropylidene-5-O-isopropyl- ⁇ -D-furanosyl fluoride was obtained at a yield of 22%.
  • Example 3 The same procedures as those conducted in Example 3 were conducted except that 2′,3′-O-isopropylideneuridine (10 mmole) was used as the substrate. As the product, 2′,3′-O-isopropylidene-5′-deoxy-5′-fluorouridine was obtained at a yield of 55%.
  • Example 3 The same procedures as those conducted in Example 3 were conducted except that N,N-diethyl- ⁇ , ⁇ -difluoro(3-methyl)benzylamine (20 mmole) was used as the substrate. As the product, 1,2,3,4-di-O-isopropylidene-6-deoxy-6-fluoro- ⁇ -D-galactopyranose was obtained at a yield of 75%.
  • the reaction product was poured into 200 ml of ice water, and the organic layer was separated.
  • the aqueous layer was treated by extraction with 50 ml of acetonitrile.
  • the obtained two organic layers were combined, washed with pure water, dried with magnesium sulfate and then filtered.
  • the obtained organic solution was concentrated using an evaporator, and the concentrated solution was analyzed in accordance with the liquid chromatography. As the result, 2.8 g (the yield: 55%) of 2-deoxy-2-fluoro- ⁇ -D-ribofuranose 1,3,5-tribenzoate of the object compound was obtained.
  • Example 2 The same procedures as those conducted in Example 1 were conducted except that 2,3,5,6-di-O-isopropylidene-D-mannofuranose (10 mmole) was used as the substrate, and the reaction was allowed to proceed at the room temperature for 1 hour. As the product, 2,3,5,6-diisopropylidene-D-mannofuranosyl fluoride was obtained at a yield of 94% without removal of the acetonide of the protective group at all.
  • Example 8 The same procedures as those conducted in Example 8 were conducted except that HF (20 mmoles) was used as the fluorinating agent. As the result, the protective group was removed, and 2,3,5,6-di-O-isopropylidene-D-mannofuranosyl fluoride of the object compound was not obtained at all. The fluorination at the 1-position could not be achieved.
  • Example 2 The same procedures as those conducted in Example 1 were conducted except that 2,3,4,5-tetra-O-acetyl-D-glucopyranose (10 mmole) was used as the substrate, and the reaction was allowed to proceed at the room temperature for 1 hour in methylene chloride. As the product, 2,3,4,5-tetra-O-acetyl-D-glucopyranosyl fluoride was obtained at a yield of 84% without removal of the acetyl group of the protective group at all.
  • Example 9 The same procedures as those conducted in Example 9 were conducted except that HF (20 mmoles) was used as the fluorinating agent. As the result, the protective group was removed, and 2,3,4,5-tetra-O-acetyl-D-glucopyranosyl fluoride of the object compound was not obtained. The fluorination at the 1-position could not be achieved.
  • Example 2 The same procedures as those conducted in Example 2 were conducted except that 2,3,4,5-tetra-O-acetyl-D-glucopyranose (10 mmole) was used as the substrate. As the product, 2,3,4,5-tetra-O-acetyl-D-glucopyranosyl fluoride was obtained at a yield of 84% without removal of the acetyl group of the protective group at all.
  • Example 7 The same procedures as those conducted in Example 7 were conducted except that ⁇ -D-ribofuranose 1,3,5-tribenzoate (11 mmole) was used as the substrate, N,N-diethyl- ⁇ , ⁇ -difluoro(2-methoxy)benzylamine (23.2 mmole) was used as the fluorinating agent, and the reaction was allowed to proceed at 120° C. for 30 minutes. As the product, 2-deoxy-2-fluoro- ⁇ -D-robofuranose 1,3,5-tribenzoate was obtained at a yield of 85%.
  • Example 9 The same procedures as those conducted in Example 9 were conducted except that D-xylopyranose (10 mmole) was used as the substrate, and a fluorination agent (80 mmole) was used. As the product, 2,3,4-tri-O-(3′-methylbenzoyl)-D-xylopyranosyl fluoride was obtained at a yield of 57%.
  • Example 6 The same procedures as those conducted in Example 6 were conducted except that N,N-diethyl- ⁇ , ⁇ -difluoro(2-methoxy)benzylamine (20 mmole) was used as the fluorinating agent, and the reaction was allowed to proceed at 120° C. for 48 hours without the irradiation with microwave. As the product, 1,2,3,4-di-O-isopropylidene-6-deoxy-6-fluoro- ⁇ -D-galactopyranosyl fluoride was obtained at a yield of 58%.
  • a 100 ml glass reactor equipped with a stirrer and a condenser and coated with a fluororesin was placed.
  • 1-dodecanol (10 mmole; 1.86 g) as the substrate and N,N-diethyl- ⁇ , ⁇ -difluoro(3-methyl)benzylamine (12 mmole; 2.25 g) as the fluorinating agent were placed. While the resultant mixture was stirred at the room temperature, the mixture was irradiated with microwave for 10 minutes.
  • the reaction was conducted in accordance with the same procedures as those conducted in Example 14 except that the irradiation with microwave was not conducted.
  • the yield of 1-fluorododecane was 45% when the reaction was allowed to proceed at a temperature of 110° C. for 10 minutes and 12% when the reaction was allowed to proceed at the room temperature for 17 hours.
  • a 100 ml glass reactor equipped with a stirrer and a condenser and coated with a fluororesin was used.
  • methyl ⁇ -hydroxyisobutyrate (10 mmole) as the substrate N,N-diethyl- ⁇ , ⁇ -difluoro(3-methyl)benzylamine (12 mmole; 2.56 g) as the fluorinating agent and 20 ml of n-heptane as the solvent were placed.
  • the reaction was allowed to proceed at 20° C. for 5 hours under stirring.
  • the yield of methyl ⁇ -fluoroisobutyrate was 80%.
  • the reaction was conducted in accordance with the same procedures as those conducted in Example 16 except that 2-(n-decyl)oxirane (10 mmole) was used as the substrate, dodecane was used as the solvent, and the irradiation with microwave was conducted for 30 minutes.
  • 1,2-difluorododecane i.e., a compound obtained by introduction of two fluorine atoms, was obtained at a yield of 65%.
  • Example 25 The same procedures as those conducted in Example 25 were conducted except that the irradiation with microwave was not conducted, and the reaction was allowed to proceed at a temperature of 115° C. for 4 hours. The yield of trans-2-fluorocyclohexanol as the product was 61%.
  • Example 26 The same procedures as those conducted in Example 26 were conducted except that the irradiation with microwave was not conducted, and the reaction was allowed to proceed at a temperature of 155° C. for 4 hours. The yield of 2-fluorocyclododecanol as the product was 54%.
  • Example 25 Using the same apparatus as that used in Example 25, the same procedures as those conducted in Example 25 were conducted except that cyclooctene oxide (1 mole) and Et 3 N-3HF (1 mole) were used, and the irradiation with microwave was conducted for 10 minutes. As the product, trans-2-fluorocyclohexanol was obtained at a yield of 68%.
  • Example 27 The same procedures as those conducted in Example 27 were conducted except that the irradiation with microwave was not conducted. The yield of trans-2-fluorocyclooctanol as the product was 54%.
  • Example 25 The same procedures as those conducted in Example 25 were conducted except that cyclododecane-1,4,8-triene monoxide (1 mole) as the substrate and Et 3 N-3HF (1 mole) were used, and the irradiation with microwave was conducted for 2 minutes. As the product, 2-fluorocyclododecane-6,10-diene-1-ol was obtained at a yield of 78%.
  • Example 28 The same procedures as those conducted in Example 28 were conducted except that the irradiation with microwave was not conducted, and the reaction was allowed to proceed at a temperature of 155° C. for 4 hours.
  • Example 25 Using the same apparatus as that used in Example 25, the fluorination under irradiation with microwave (Examples) and the fluorination in accordance with the thermal reaction (Comparative Examples) were compared using the substrates and the fluorinating agents shown in Table 1. The results are shown in Table 1.
  • Example 25 The same procedures as those conducted in Example 25 were conducted except that 3-phenylpropyl methyl sulfonate (1 mmole) and Et 3 N-3HF (1.2 mmole) were placed in a 10 ml reactor made of PFA, and the irradiation with microwave was conducted for 2 minutes. As the product, 1-fluoro-3-phenylpropane was obtained at a yield of 80%.
  • the yield after 10 hours 12%
  • the yield after 20 hours 20%
  • Example 31 triethylamine-3HF room temp. 5 94 Comparative Example 14 triethylamine-3HF 60 360 91 (Fluorination with removal of diazo group): benzene diazoniumtetrafluoroborate to fluorobenzene Example 32 triethylamine-3HF room temp.
  • the fluorination of various substrates which are hardly fluorinated in accordance with the conventional technology can proceed highly selectively, efficiently in a short time and safely.
  • the substrates are, for example, saccharides useful as the functional chemical such as materials for drugs, cosmetics and healthy foods, compounds having hydrogen atom activated by a substituent at the ⁇ position, the ⁇ -position or the ⁇ -position, silyl ether compounds, compounds having an unsaturated group, hydroxyl group, a halogeno group, amino group, diazo group, triazeno group or isocyano group as the functional group, and cyclic compounds having three-membered or greater ring which may have heteroatoms.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Saccharide Compounds (AREA)
US10/537,437 2002-12-04 2003-12-01 Method of fluorination Expired - Fee Related US7351863B2 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US12/068,500 US7892518B2 (en) 2002-12-04 2008-02-07 Method of fluorination
US12/068,481 US7968751B2 (en) 2002-12-04 2008-02-07 Method of fluorination

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
JP2002-352968 2002-12-04
JP2002352968A JP4577478B2 (ja) 2002-12-04 2002-12-04 糖質のフッ素化方法
JP2002358249A JP2004189655A (ja) 2002-12-10 2002-12-10 マイクロ波によるフッ素化方法
JP2002-358249 2002-12-10
PCT/JP2003/015336 WO2004050676A1 (fr) 2002-12-04 2003-12-01 Procede de fluoration

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US12/068,481 Division US7968751B2 (en) 2002-12-04 2008-02-07 Method of fluorination
US12/068,500 Division US7892518B2 (en) 2002-12-04 2008-02-07 Method of fluorination

Publications (2)

Publication Number Publication Date
US20060014972A1 US20060014972A1 (en) 2006-01-19
US7351863B2 true US7351863B2 (en) 2008-04-01

Family

ID=32473692

Family Applications (3)

Application Number Title Priority Date Filing Date
US10/537,437 Expired - Fee Related US7351863B2 (en) 2002-12-04 2003-12-01 Method of fluorination
US12/068,481 Expired - Fee Related US7968751B2 (en) 2002-12-04 2008-02-07 Method of fluorination
US12/068,500 Expired - Fee Related US7892518B2 (en) 2002-12-04 2008-02-07 Method of fluorination

Family Applications After (2)

Application Number Title Priority Date Filing Date
US12/068,481 Expired - Fee Related US7968751B2 (en) 2002-12-04 2008-02-07 Method of fluorination
US12/068,500 Expired - Fee Related US7892518B2 (en) 2002-12-04 2008-02-07 Method of fluorination

Country Status (3)

Country Link
US (3) US7351863B2 (fr)
EP (3) EP2189466A3 (fr)
WO (1) WO2004050676A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080154064A1 (en) * 2002-12-04 2008-06-26 Shoji Hara Method of fluorination
US20100130790A1 (en) * 2007-03-23 2010-05-27 Im&T Research, Inc. Methods for Producing Fluorinated Phenylsulfur Pentafluorides
US20110004022A1 (en) * 2007-03-23 2011-01-06 Im&T Research, Inc. Process for Producing Arylsulfur Pentafluorides
US20110009672A1 (en) * 2006-07-28 2011-01-13 Im&T Research, Inc. Substituted Phenylsulfur Trifluoride and Other Like Fluorinating Agents
US20110160488A1 (en) * 2008-03-07 2011-06-30 I M &T Research, Inc. Fluorination Processes with Arylsulfur Halotetrafluorides
US20110166392A1 (en) * 2008-09-22 2011-07-07 Ube Industries, Ltd. Processes for Preparing Poly(Pentafluorosulfanyl)Aromatic Compounds
US20110190511A1 (en) * 2008-08-18 2011-08-04 Im&T Research, Inc. Methods For Preparing Fluoroalkyl Arylsulfinyl Compounds And Fluorinated Compounds Thereto
US8203003B2 (en) 2009-01-09 2012-06-19 Ube Industries, Ltd. 4-fluoropyrrolidine-2-carbonyl fluoride compounds and their preparative methods

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4752759B2 (ja) * 2004-03-04 2011-08-17 三菱瓦斯化学株式会社 光学活性フルオロ化合物の製造方法
CN101061090B (zh) * 2004-11-05 2011-06-15 国立大学法人北海道大学 α,α-二氟胺的制备方法
US8051023B2 (en) * 2007-08-23 2011-11-01 Rodney Kellogg System, method and computer program product for interfacing a decision engine and marketing engine
US8954367B2 (en) 2007-08-23 2015-02-10 Dside Technologies, Llc System, method and computer program product for interfacing software engines
WO2009051162A1 (fr) * 2007-10-17 2009-04-23 National University Corporation Hokkaido University Procédé de production d'un composé cyclique bicyclo
US8030516B2 (en) * 2007-10-19 2011-10-04 Ube Industries, Ltd. Methods for producing perfluoroalkanedi(sulfonyl chloride)
WO2009076345A1 (fr) * 2007-12-11 2009-06-18 Im & T Research, Inc. Procédés et compositions pour la fabrication de composés contenant du difluorométhylène et du trifluorométhyle
US20100174096A1 (en) * 2009-01-05 2010-07-08 Im&T Research, Inc. Methods for Production of Optically Active Fluoropyrrolidine Derivatives
MX2015005949A (es) 2012-11-16 2015-09-08 Biocryst Pharm Inc Nucleosidos que contienen aza-azucar antiviral.
CN114507115B (zh) * 2022-01-21 2023-08-15 浙江诺亚氟化工有限公司 一种由氟化环氧化物制备氟烷烃化合物的方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3101357A (en) 1962-03-09 1963-08-20 Syntex Corp 19-halo androstenes
WO1997041083A1 (fr) 1996-05-01 1997-11-06 Rhodia Limited Procede de preparation de composes fluores a partir des amines correspondantes
WO2000058240A1 (fr) 1999-03-31 2000-10-05 Rhodia Chimie Procede d'activation de substrats aromatiques par micro-ondes
WO2001002320A1 (fr) 1999-07-02 2001-01-11 Rhodia Chimie Utilisation de nitriles comme solvants aprotiques polaires
EP1172369A1 (fr) 2000-07-13 2002-01-16 Air Products And Chemicals, Inc. Synthèse de dérivés de 2-déoxy-2-fluoro-arabinose
JP2003064034A (ja) 2001-08-28 2003-03-05 Mitsubishi Gas Chem Co Inc フッ素化合物及び該フッ素化合物からなるフッ素化剤

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2189466A3 (fr) 2002-12-04 2010-09-08 Mitsubishi Gas Chemical Company, Inc. Procédé de fluoration par micro-ondes
JP4752759B2 (ja) * 2004-03-04 2011-08-17 三菱瓦斯化学株式会社 光学活性フルオロ化合物の製造方法

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3101357A (en) 1962-03-09 1963-08-20 Syntex Corp 19-halo androstenes
WO1997041083A1 (fr) 1996-05-01 1997-11-06 Rhodia Limited Procede de preparation de composes fluores a partir des amines correspondantes
WO2000058240A1 (fr) 1999-03-31 2000-10-05 Rhodia Chimie Procede d'activation de substrats aromatiques par micro-ondes
WO2001002320A1 (fr) 1999-07-02 2001-01-11 Rhodia Chimie Utilisation de nitriles comme solvants aprotiques polaires
EP1172369A1 (fr) 2000-07-13 2002-01-16 Air Products And Chemicals, Inc. Synthèse de dérivés de 2-déoxy-2-fluoro-arabinose
JP2003064034A (ja) 2001-08-28 2003-03-05 Mitsubishi Gas Chem Co Inc フッ素化合物及び該フッ素化合物からなるフッ素化剤
US7019173B2 (en) * 2001-08-28 2006-03-28 Mitsubishi Gas Chemical Company, Inc. Fluorine compound and fluorinating agent comprising the compound

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
Chirakal et al., "Base-mediated Decomposition of a Mannose Triflate During the Synthesis of 2-Deoxy-2-18F-fluoro-D-glucose" Applied radiation and isotopes (1995) vol. 46, No. 3, pp. 149-155. *
Dmowski et al., "Reactions of N,N-dialkylbenzamides with Sulfur Tetrafluoride, Formation of Dlalkyl-alpha,alpha-Difluorobenzylamines" Polish Journal of Chemistry (1982) vol. 56, pp. 1369-1378. *
Dmowski et al., Dialkyl alpha,alpha-difluorobenzylamines and dialkyl(trifluoromethyl)-amines-Novel Fluorinating Reagents Journal of Fluorine Chemistry (1983) vol. 23, pp. 219-228. *
Edited by CSJ: The Chemical Society of Japan, "Shin Jikken Kagaku Koza 14 Yuki Kagobutsu No. Gosel to Han'no [1]", (publisher Maruzen Co., Ltd.), 1977, pp. 308-331.
Journal of Flourine Chemisitry vol. 23, Sep. 3, 1983 ISSN 0021139 pp. 219-228.
Tetrahedron Letters, vol. 27, No. 3, pp. 279-282, 1986.
U.S. Appl. No. 10/591,698, filed Sep. 2006, Hara, Shoji. *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080154064A1 (en) * 2002-12-04 2008-06-26 Shoji Hara Method of fluorination
US20080319228A1 (en) * 2002-12-04 2008-12-25 Shoji Hara Method of fluorination
US7892518B2 (en) * 2002-12-04 2011-02-22 Mitsubishi Gas Chemical Company, Inc. Method of fluorination
US7968751B2 (en) * 2002-12-04 2011-06-28 Mitsubishi Gas Chemical Company, Inc. Method of fluorination
US9365471B2 (en) 2006-07-28 2016-06-14 Ube Industries, Ltd. Substituted phenylsulfur trifluoride and other like fluorinating agents
US8710270B2 (en) 2006-07-28 2014-04-29 Ube Industries, Ltd. Substituted phenylsulfur trifluoride and other like fluorinating agents
US20110009672A1 (en) * 2006-07-28 2011-01-13 Im&T Research, Inc. Substituted Phenylsulfur Trifluoride and Other Like Fluorinating Agents
US20110004022A1 (en) * 2007-03-23 2011-01-06 Im&T Research, Inc. Process for Producing Arylsulfur Pentafluorides
US20100130790A1 (en) * 2007-03-23 2010-05-27 Im&T Research, Inc. Methods for Producing Fluorinated Phenylsulfur Pentafluorides
US8399720B2 (en) 2007-03-23 2013-03-19 Ube Industries, Ltd. Methods for producing fluorinated phenylsulfur pentafluorides
US8987516B2 (en) 2007-03-23 2015-03-24 Ube Industries, Ltd. Process for producing arylsulfur pentafluorides
US20110160488A1 (en) * 2008-03-07 2011-06-30 I M &T Research, Inc. Fluorination Processes with Arylsulfur Halotetrafluorides
US20110190511A1 (en) * 2008-08-18 2011-08-04 Im&T Research, Inc. Methods For Preparing Fluoroalkyl Arylsulfinyl Compounds And Fluorinated Compounds Thereto
US20110166392A1 (en) * 2008-09-22 2011-07-07 Ube Industries, Ltd. Processes for Preparing Poly(Pentafluorosulfanyl)Aromatic Compounds
US8653302B2 (en) 2008-09-22 2014-02-18 Ube Industries, Ltd. Processes for preparing poly(pentafluorosulfanyl)aromatic compounds
US8203003B2 (en) 2009-01-09 2012-06-19 Ube Industries, Ltd. 4-fluoropyrrolidine-2-carbonyl fluoride compounds and their preparative methods

Also Published As

Publication number Publication date
EP2189466A3 (fr) 2010-09-08
WO2004050676A1 (fr) 2004-06-17
EP2189466A2 (fr) 2010-05-26
US7892518B2 (en) 2011-02-22
US20060014972A1 (en) 2006-01-19
EP1568703A4 (fr) 2008-04-02
EP2189467A2 (fr) 2010-05-26
EP2189467A3 (fr) 2010-09-08
US20080319228A1 (en) 2008-12-25
US7968751B2 (en) 2011-06-28
EP1568703A1 (fr) 2005-08-31
US20080154064A1 (en) 2008-06-26

Similar Documents

Publication Publication Date Title
US7892518B2 (en) Method of fluorination
RU2505543C2 (ru) Твердые формы (2s,3r,4r,5s,6r)-2-(4-хлор-3-(4-этоксибензил)фенил)-6-(метилтио)тетрагидро-2н-пиран-3,4,5-триола и способы их применения
CA1258452A (fr) Procede de synthese organique d'oligosaccharides renfermant des motifs galactosamine-acide-uronique, oligosaccharides obtenus et leurs applications biologiques
RU2315769C9 (ru) Нуклеофильное фторирование в твердой фазе
EP1440077B1 (fr) Pentasaccharides hepariniques synthetiques
Lehmann et al. The plant sulfolipid. IX. Sulfosugar syntheses from methyl hexoseenides
Numata et al. An efficient synthesis of ganglioside GM3: highly stereocontrolled glycosylations by use of auxiliaries
HARADAHIRA et al. Synthesis of 2-deoxy-2-fluoro-D-mannose using fluoride ion
KR880001867B1 (ko) 당 케탈류의 제조방법
JP4577478B2 (ja) 糖質のフッ素化方法
Koreeda et al. Z-Stereoselective Wittig olefination of 2-oxygenated cyclohexanones
KR100908570B1 (ko) 3-플루오로-1,3-프로판설톤의 제조방법
JP2004189655A (ja) マイクロ波によるフッ素化方法
JP2004123605A (ja) フッ素化方法
EP1506958A1 (fr) Procede de production de shogaol et produits intermediaires servant a la synthese de shogaol
Fang et al. Synthesis of Substituted 2, 6-Dioxabicyclo [3.1. 1] Heptanes: 1, 3-Anhydro-2, 4-DI-O-Benzyl and 1, 3-Anhydrq-2, 4-DI-O-(p-Bromobenzyl)-β-D-Rhamnopyranose
EP0819697A2 (fr) 1-C-perfluoroalkyl glycosides, procédé de préparation et utilisations
Wegert et al. Synthesis of 2, 3-or 1, 2-unsaturated derivatives of 2-deoxy-2-trifluoromethylhexopyranoses
RU2443680C2 (ru) Способ получения n-(1-адамантил)ацетамида
JP2670574B2 (ja) 同位元素標識アルドノニトリル誘導体
US6590110B1 (en) Method for synthesizing C-glycosides of ulosonic acids
JP4064451B2 (ja) コンズリットエポキシドおよびアジリジンの合成およびそれらの高度二糖類の合成への利用方法
Andreev et al. [3, 3]-Sigmatropic rearrangements of fluorocarbanions
Eilitz et al. Synthesis of homochiral 2-C-perfluoroalkyl substituted d-and l-riboses
李艳茹 Site-selective C (sp3)–H Alkylation of Saccharide Derivatives by Photocatalysts

Legal Events

Date Code Title Description
AS Assignment

Owner name: MITSUBISHI GAS CHEMICAL COMPANY, INC., JAPAN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:HARA, SHOJI;FUKUHARA, TSUYOSHI;REEL/FRAME:017078/0614

Effective date: 20050520

FEPP Fee payment procedure

Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

FPAY Fee payment

Year of fee payment: 4

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20160401